Introduction Prior research indicates methylphenidate (MPH) and alcohol (ethanol, EtOH) interact to significantly affect responses humans and mice. The present studies tested the hypothesis that MPH and EtOH interact to potentiate ethanol-related behaviors in mice. Methods We used several behavioral tasks including: drug discrimination in MPH-trained and EtOH-trained mice, conditioned place preference (CPP), rota-rod and the parallel rod apparatus. We also used gas chromatographic methods to measure brain tissue levels of EtOH and the d and l isomers of MPH and the metabolite, ethylphenidate (EPH). Results In discrimination, EtOH (1g/kg) produced a significant leftward shift in the MPH generalization curve (1-2mg/kg) for MPH-trained mice, but no effects of MPH (0.625-1.25mg/kg) on EtOH discrimination in EtOH-trained mice (0-2.5g/kg) were observed. In CPP, the MPH (1.25mg/kg) and EtOH (1.75g/kg) combination significantly increased time on the drug paired side compared to vehicle (30.7%), but this was similar to MPH (28.8%) and EtOH (33.6%). Footslip errors measured in a parallel rod apparatus indicated that the drug combination was very ataxic, with footslips increasing 29.5% compared to EtOH. Finally, brain EtOH concentrations were not altered by 1.75g/kg EtOH combined with 1.25mg/kg MPH. However, EtOH significantly increased d-MPH and l-EPH without changing l-MPH brain concentrations. Conclusions The enhanced behavioral effects when EtOH is combined with MPH are likely due to the selective increase in brain d-MPH concentrations. These studies are consistent with observations in humans of increased interoceptive awareness of the drug combination and provide new clinical perspectives regarding enhanced ataxic effects of this drug combination.

Methylphenidate (MPH) remains an important therapy for Attention-Deficit Hyperactivity Disorder but aspects of its pharmacology remain unclear. In the present study, we used a regimen of MPH (8 mg/kg daily X 14 days) in C57BL/6J mice to determine whether establishing locomotor sensitization to MPH influenced the acquisition and the dose-response function of MPH in a classic drug discrimination procedure. MPH-sensitized mice (SENS group) demonstrated enhanced locomotor activity to the 8 mg/kg exposure dose as well as a 2mg/kg dose prior to discrimination training. However, the SENS mice did not acquire discrimination of either a low dose (2mg/kg) or a higher dose (4mg/kg) of MPH any more rapidly than the CTRL mice. Further, during generalization testing, the dose-response functions for the SENS and CTRL mice were identical. Therefore, we did not find that prior exposure to MPH, which produced a sensitized locomotor response, facilitated MPH discrimination.

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Methylphenidate, (MPH), is commonly prescribed for attention deficit/hyperactivity disorder (ADHD). It is similar to cocaine in that it inhibits the dopamine transporter to elevate extracellular dopamine levels and has reinforcing effects. As ADHD diagnoses have increased, MPH abuse has increased as well. There is evidence that DA antagonists such as Clozapine may be effective in mitigating cocaine abuse. Therefore, it is hypothesized that Clozapine will inhibit the rewarding effects of MPH in a conditioned place preference (CPP) paradigm. The data showed that both MPH and Clozapine treated groups had a significant aversion to the drug-paired compartment. Because MPH produced a conditioned aversion, the effect of Clozapine on the rewarding effects of MPH remains to be elucidated. Future studies using lower doses of MPH, as well as those analyzing dopamine levels in the striatum and prefrontal cortex would provide evidence of the effect of Clozapine on mesolimbic dopamine systems.

Symptoms of Attention Deficit Hyperactive Disorder (ADHD) include hyperactivity, inattentiveness, and impulsivity, which are caused by dopamine dysfunction in the medial prefrontal cortex.  A six-hydroxydopamine lesion model of ADHD was used to examine response accuracy on an attentional task under one of three conditions: cue only, methylphenidate only (MPH), and MPH with cue.  Results indicated rats injected with methylphenidate and exposed to an external cue showed a significant increase in response accuracy compared to the MPH and cue only groups.  Also, the results indicate animals in the cue only condition had an increase performance in response accuracy compared to just methylphenidate group.  This study provides evidence that combination of a stimulant and external cue would have a stronger affect than a stimulant or external cue was given alone. Keywords: dopamine, hyperactivity, methylphenidate, external cue, medial prefrontal cortex